SGLT2 Inhibitors Boost Cardiac Energy Through PANK1

Key Points

• SGLT2 inhibitors directly activate PANK1, an enzyme involved in coenzyme A (CoA) production in heart cells.
• Increased CoA levels help failing heart cells use multiple fuel sources more efficiently.
• Activating the PANK1 pathway improved contraction and relaxation in human heart cells.
• The findings may explain how SGLT2 inhibitors produce heart failure benefits within days of treatment.
• Direct PANK1-targeting therapies could potentially provide cardiac benefits while reducing some adverse effects associated with SGLT2 inhibitors.
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How Do SGLT2 Inhibitors Improve Heart Function?

SGLT2 inhibitors may improve failing heart function by directly activating a metabolic enzyme called PANK1, according to a study published in Science. Researchers from the Perelman School of Medicine at the University of Pennsylvania found that this mechanism increases production of coenzyme A (CoA), a molecule essential for cellular energy metabolism.

SGLT2 inhibitors were originally developed to manage diabetes but have become an important therapy for heart failure because they reduce hospitalizations and cardiovascular deaths. However, their direct cardiac mechanism has remained unclear because the drugs were designed to target SGLT2 proteins primarily found in the kidneys.

The new findings suggest that their benefits extend beyond glucose and kidney-related pathways. By activating PANK1 in heart cells, these medications appear to improve the heart’s capacity to generate and use energy.

PANK1 Activation Supports Cardiac Energy Metabolism

Researchers examined human heart tissue obtained from transplant recipients and donors to determine how SGLT2 inhibitors affect cardiac metabolism. The drugs increased the heart’s ability to use several energy sources, including sugars, fatty acids, amino acids, and ketones.

The team also observed increased CoA levels. Because PANK1 controls the first major step in CoA production, researchers investigated whether the enzyme represented a direct drug target.

Their experiments demonstrated that SGLT2 inhibitors physically bind to and activate PANK1. Increasing PANK1 activity alone reproduced several effects associated with the medications, while blocking the pathway substantially reduced those benefits.

Importantly, increased CoA production improved the contraction and relaxation of human heart cells, functions that become impaired during heart failure. The mechanism may therefore help explain why patients can experience cardiovascular benefits soon after beginning SGLT2 inhibitor therapy.

Could PANK1 Become a New Heart Failure Target?

The discovery identifies PANK1 as a potential therapeutic target for heart failure treatment. Researchers suggest that drugs designed to directly activate PANK1 could potentially reproduce some cardiac benefits of SGLT2 inhibitors without triggering their kidney-related effects.

Although SGLT2 inhibitors are generally well established in heart failure care, they can cause adverse effects such as urinary tract infections, dehydration, and, rarely, diabetic ketoacidosis. Direct PANK1-targeting therapies could therefore represent a future strategy for improving cardiac energy metabolism while potentially limiting some treatment-related risks.

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For cardiologists, heart failure specialists, and other HCPs, the findings provide a new perspective on the metabolic mechanisms underlying SGLT2 inhibitor therapy and highlight the importance of cardiac energy utilization in heart failure management.

Source:

University of Pennsylvania School of Medicine